Oxygen plays an important role in producing ATP by oxidizing nutrients at the mitochondria inside cells. However, inevitably, 2–5% of the oxygen changes into reactive oxygen species such as superoxide radical(.O2−), hydrogen peroxide(H2O2) and hydroxy radical(HO.) that are harmful to human body.
As a protector against reactive oxygen species, antioxidant enzymes such as superoxide dismutase, catalase and peroxidase, and antioxidant substances such as glutathion and coenzyme Q (CoQ) are present in vivo, and such antioxidant substances can also be intake with food. However, under specific circumstances such as ischemia, too much active oxygen is generated, which exceeds the biological protect system capacity to cause oxidative stress. Such active oxygen attacks the biological cell to destroy lipid, protein and RNA, DNA, and inhibits various enzymes to cause cancer, neurodegerative diseases and cardiovascular diseases and aging.
Thus, antioxidants which eliminate active oxygen or inhibit the generation of active oxygen can not only be used as age resisters or anti cancer drugs, but as therapeutics for various neurodegerative diseases such as dementia and ischemic stroke.
More particularly, active oxygen shows a non-selective, non-reversible destructive reaction against cell components such as lipid, protein, sugar and DNA. Hereupon, enzymes that are naturally generated from low density lipoproteins or plasma protect cells from being oxidized. The prevention of lipid peroxidation is a basic reaction for breathing organisms, and thus, organisms undergoing organic respiration have a defense system that defends the organism from ROS generated by the oxidation reaction of respiration and substrate. A little amount of ROS (.OH, .O2−, H2O2), or even nitric oxide (NO) and peroxinitrite (ONOO) are continuously generated in the process of respiration by receiving both internal and external stimuli. When the ROS level is low, it plays an important role in protecting it from microorganims or in the biochemical processes of the immune system, cell differentiation, and internal signal transduction. However, on the contrary, when the ROS level exceeds the amount that can be managed in vivo, it is biologically damaged and builds up oxidative stress such as dysfunction in metabolism. If such oxidative toxicity is not eliminated, it damages DNA and inhibits the production of proteins such as Na+/K′ ATPases and glutamate transporter. Further, if lipid peroxidation increases and the activity of antioxidants decreases, the nuclear center of the cell gets attacked and damages the protein, DNA and RNA to display allergy, variability or herpes virus.
Oxidative stress of ROS which causes such damages can be explained by referring to various pathologic symptoms derived at the central nervous system (CNS), and physical processes such as neurodegerative diseases and aging. The reason ROS is especially fatal to neurodegerative diseases is because the metabolic velocity of oxygen is very high in nervous systems, and the antioxidation degree which defends oxidation maintains a low level. Further, since it contains a high level of unsaturated fatty acid and transition metal, it is very sensitive to oxidation stress. Therefore, if ROS production increases and is not eliminated, cell macromolecules are damaged to a large extent. Accordingly, DNA or protein, lipid are damaged to generate structural, functional abnormal phenomenon. Especially, brain lipid damage due to lipid peroxidation causes fatal neurodegerative diseases.
Such neurodegerative diseases can be classified as acute diseases and chronic diseases. Acute neurodegerative diseases include ischemic stroke, subarachnoid hemorrhage, trauma to the brain and spinal cord, and chronic neurodegerative diseases include Alzheimer's disease, Parkinson's disease, and Huntington's disease. Among these, the mortality rate caused by stroke tends to increase every year all over the world, let alone in Korea.
The field wherein the development of therapeutics for ischemic stroke is being researched most actively is the field of glutamate receptor antagonist. Such therapeutics includes N-methyl-D-aspartate receptor antagonist (NMDA), α-amino-3-hydroxy-4-isoxazole propionic acid receptor antagonist (AMPA), γ-aminobutyric acid (GABA), calcium channel blocker and sodium channel blocker. Recently, research on developing ischemic stroke therapeutics using antioxidants is being performed [Barr, P. R.; Flint Beal, M. Neuroprotection in CNS Diseases; Marcel Dekker Inc.].
For a long period of time, antioxidants which eliminate substances harmful to human body have been successively used in protecting synthetic materials or food from being oxidized. Recently, research on antioxidants used as neuro-protecting drugs for various diseases such as Parkinson's disease, Alzheimer's diseases, stroke and traumatic injury is being performed. Antioxidants maintain the active oxygen generated during the respiration process in our body to a certain level as stated above, and treat the ROS free radical by the mutual combination system of antioxidants such as antioxidant enzymes (AOEs), endogenous organic compounds including reduced glutathion or GSH, ubiquinone or coenzyme Q, NADPH, melatonine, uric acid, trace minerals including Se, Zn and Mn, and vitamins including vitamin A, C, and E. However, when diseases are caused by the production of excessive amount of ROS due to the trouble in the system, chemically synthesized antioxidants are used in order to solve such problems. As for antioxidants synthesized as above, BHT (tert-butyl-hydroxytoluene), Idebenone or antioxidative substances of Carbozole and Phenazine have already been developed. [Okamoto, K.; Wasazumi, M.; Morimoto, H.; Imada, I. Chem. Pharm. Bull. 1988, 36, 178. Yamaguchi, T.; Sano, K.; Takakura, K.; Saito, I.; Shinohara, Y.; Asano, T.; Yasuhara, H. Stroke 1998, 29, 12. Dirnagl. U.; Iadecola, C.; Moskowitz, M. A. TINS 1999, 22, 391.].